Radioprotection, pharmacokinetic and behavioural studies in mouse implanted with biodegradable drug (amifostine) pellets

Abstract

Amifostine in biodegradable implant was effective. The radioprotection observed was comparable between conventional s.c. administration of the drug and implantation. Pharmacokinetic data and locomotor activity suggest that the implantation was beneficial though radioprotection data warrants formulation improvements in implants.

Radioprotection of hematopoietic progenitors by low dose amifostine prophylaxis

“…These efforts include attempts to (a) chemically reengineer amifostine into a new, better tolerated analog (Davidson et al 1980, Brown et al 1988); (b) improve methods and vehicles of drug delivery (Fatome et al 1987, Srinivasan et al 2002, Pamujula et al 2004); (c) foster radioprotective synergy by supplementing lower doses amifostine with less toxic (but generally less protective) protectants (e.g., alpha-tocopherol) (Srinivasan et al 1992); (d) control amifostine toxicity by direct pharmacologic means (i.e., use of antiemetics) (Seed et al unpublished observations); and (e) use very low, presumably non-toxic doses of amifostine solely for the purpose of protecting against radiation-induced mutatagenesis and/or carcinogenesis, while foregoing the drug’s cytoprotective attributes that requires much higher, more toxic doses to be delivered (Grdina et al 2002). …”

Radioprotection of Osteoblasts by a Fractionated Dose Regimen and Amifostine

“…Our use of 4 mM amifostine treatment of in vitro osteoblasts is within the same order magnitude of high-performance liquid chromatography-measured in vivo radioprotective doses. 28,29 Clearly, increases (or decreases) in radiation dose will alter the concentration at which amifostine is radioprotective; further doseresponse studies will elucidate tissue-specific guidelines.…”

Sustained-release microspheres of amifostine for improved radio-protection, patient compliance, and reduced side effects

“…It is noteworthy to mention the investigation conducted by Srinivasan et al (2002), in which the authors discovered that the use of a subcutaneously implantable, biodegradable pellet of amifostine was highly effective in radiation protection (Srinivasan et al, 2002). Their study results indicated that the amifostine dose of 100 mg/kg given through a pellet induced a response that was identical to a dose of up to 300 mg/kg of amifostine administrated by conventional IV route (Kuna et al, 1983).…”

“…Investigation by Srinivasan et al (2002) also shown that 1h to 2h was the optimal time for pellet implantation as the mice 30-day survival rate was 100% and 95% when subcutaneous biodegradable pellet implantation was done 1h and 2h before irradiation (Srinivasan et al, 2002).…”

“…A welldesigned sustained-release dosage form may help to maintain a sustained effective blood concentration of the drug, which was reported to have a narrow therapeutic index (Rick et al, 2001;Levi et al, 2002;McKibbin et al, 2010;Zois et al, 2011), and at the same time avoid the intensive local concentration. In fact, such benefits of a sustained-release administration of the drug have been demonstrated by subcutaneous implanting of biodegradable amifostine pellets (Srinivasan et al, 2002). Quite clearly, an injectable sustained-release microsphere dosage form able to maintain fairly steady blood concentration should be an ideal solution to resolve the problems and concerns encountered in the radioprotective cancer therapy involving the application of amifostine.…”